Ataxia telangiectasia (A-T) results from mutation of the ATM gene. Individuals with an ATM mutation in one allele are spared from most of the symptoms of the disease, but are more susceptible to cancer and ischemic heart disease. ATM gene encodes a protein kinase which is suggested to be a key regulator of signaling cascades involved in cell cycle checkpoints, DNA repair and apoptosis. Evidence has been provided that inhibition of ATM induces a switch from apoptosis to necrosis in murine embryonic fibroblasts. Cardiac myocyte loss due to apoptosis and necrosis plays a significant role in the development of contractile dysfunction in the failing heart. Regulation of ATM gene expression and activity in postmitotic cardiac myocytes, and its role in apoptosis, necrosis and myocardial remodeling is not known. Analysis of differential expression of apoptosis-related genes using Gene-Array technique (preliminary data) revealed that 2-AR stimulation increases ATM gene expression. RT-PCR, western blot and immunocytochemical analyses demonstrated increased ATM expression in isolated adult cardiac myocytes and heart after 2-AR stimulation and myocardial infarction. 2-AR stimulation increased p53 protein (a downstream target of ATM) levels in the heart, and inhibition of ATM and p53 reduced 2-AR-stimulated apoptosis. Other preliminary data obtained using ATM deficient mice and chronic 2-AR-stimulation as a model of myocardial remodeling demonstrated that deficiency of ATM decreases left ventricular (LV) percent fractional shortening and ejection fraction, and increases LV end-systolic diameter and fibrosis. Increased myocardial fibrosis indicates increased cardiac cell necrosis and inflammation. Preliminary data suggested increased macrophage infiltration in the myocardium and increased necrosis in myocytes isolated from the myocardium of ATM deficient mice as compared to wild-type (WT) mice following 2-AR stimulation. These observations have led to our hypothesis that increased ATM expression and activity plays a pro-apoptotic role via p53-dependent mechanism/s. Deficiency of ATM induces a switch from cardiac myocyte apoptosis to necrosis leading to increased susceptibility to ischemic heart disease. Aim 1 will determine in vivo the role of ATM in myocardial remodeling using (WT) and ATM deficient mice subjected to A) isoproterenol infusion, B) myocardial infarction. Aim 2 studies will provide an insight into the mechanism by which ATM modulates cardiac cell death (necrosis and apoptosis) using myocytes isolated from the myocardium of adult WT and ATM deficient mice. Aim 3 will investigate the proximal signaling pathway (21-AR-Gs and GSK-32-JNKs) leading to increased expression and activity of ATM using pharmacological inhibitors and adenovirus-mediated gene transfer. These studies may help to uncover therapeutic targets to treat ischemic heart disease in AT patients. PUBLIC HEALTH RELEVANCE: Loss or inactivation of ATM protein in the human genetic disorder ataxia-telangiectasia (AT) leads to pleiotropic phenotype, including neuronal degeneration, immunodeficiency, genomic instability, premature aging and cancer predisposition. Individuals with an ATM mutation in one allele are spared from most of the symptoms of the disease, but are more susceptible to cancer and ischemic heart disease. The proposed studies, designed to investigate the role of ATM in cardiac myocyte loss and myocardial remodeling, could identify molecular targets to treat ischemic heart disease in AT patients.